Antibody Fc-chimerism and effector functions: When IgG takes advantage of IgA

Recent advances in the development of therapeutic antibodies (Abs) have greatly improved the treatment of otherwise drug-resistant cancers and autoimmune diseases. Antibody activities are mediated by both their Fab and the Fc. However, therapeutic Abs base their protective mechanisms on Fc-mediated effector functions resulting in the activation of innate immune cells by FcRs. Therefore, Fc-bioengineering has been widely used to maximise the efficacy and convenience of therapeutic antibodies. Today, IgG remains the only commercially available therapeutic Abs, at the expense of other isotypes. Indeed, production, sampling, analysis and related in vivo studies are easier to perform with IgG than with IgA due to well-developed tools. However, interest in IgA is growing, despite a shorter serum half-life and a more difficult sampling and purification methods than IgG. Indeed, the paradigm that the effector functions of IgG surpass those of IgA has been experimentally challenged. Firstly, IgA has been shown to bind to its Fc receptor (FcR) on effector cells of innate immunity with greater efficiency than IgG, resulting in more robust IgA-mediated effector functions in vitro and better survival of treated animals. In addition, the two isotypes have been shown to act synergistically. From these results, new therapeutic formats of Abs are currently emerging, in particular chimeric Abs containing two tandemly expressed Fc, one from IgG (Fc gamma) and one from IgA (Fc alpha). By binding both Fc gamma R and Fc alpha R on effector cells, these new chimeras showed improved effector functions in vitro that were translated in vivo. Furthermore, these chimeras retain an IgG-like half-life in the blood, which could improve Ab-based therapies, including in AIDS. This review provides the rationale, based on the biology of IgA and IgG, for the development of Fc gamma and Fc alpha chimeras as therapeutic Abs, offering promising opportunities for HIV-1 infected patients. We will first describe the main features of the IgA- and IgG-specific Fc-mediated signalling pathways and their respective functional differences. We will then summarise the very promising results on Fc gamma and Fc alpha containing chimeras in cancer treatment. Finally, we will discuss the impact of Fc alpha-Fc gamma chimerism in prevention/treatment strategies against infectious diseases such as HIV-1.

Automated summary

Recent advances in therapeutic antibodies have greatly improved the treatment of drug-resistant cancers and autoimmune diseases. Fc-bioengineering has been widely used to enhance the efficacy and convenience of therapeutic antibodies, although IgG remains the most commercially available. However, interest in IgA is growing due to its enhanced binding to Fc receptors and potential synergistic effects with IgG.